USP18 attenuates endoplasmic reticulum stress via the PERK-eIF2α-ATF4 axis to reduce apoptosis in hepatocellular carcinoma cells

Ubiquitin-specific peptidase 18 (USP18) is a specific interferon-stimulated gene 15 demodifying enzyme that plays an important role in Apoptosis. In this study, we investigated the role of USP18 in Apoptosis in hepatocellular carcinoma cells, especially its ability to regulate Apoptosis through endoplasmic reticulum (ER) stress. We found that protein levels of Bcl-2-associated protein x and cytochrome c were down-regulated by USP18, which suppressed the classical mitochondrial-mediated Apoptosis pathway. USP18 also inhibited Apoptosis through the unfolded protein response (UPR) pathway by inhibiting the phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and the expression of CCAAT/enhance-binding protein homologous protein, which is a downstream marker molecule of ER stress. The UPR triggered by ER stress eventually led to the cleavage of downstream effecter proteases, including Caspase-3, leading to Apoptosis. Furthermore, USP18 combined with a PERK agonist regulated Apoptosis through the PERK-eukaryotic initiation factor-2α-activating transcription factor 4 axis of the UPR. Our results show that USP18 participates in the regulation of hepatocellular carcinoma cell Apoptosis through different pathways, especially the ER stress pathway, and that it plays a complex role in cell stress responses and Apoptosis regulation.

Apoptosis; Endoplasmic reticulum stress; Hepatocellular carcinoma; Protein kinase RNA-like Endoplasmic reticulum kinase; Ubiquitin-specific peptidase 18.